Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis

Inclusion Criteria:

1. Capable of giving signed informed consent, which includes compliance with the
requirements and restrictions, listed in the informed consent form (ICF) and in
protocol.

2. Provision of signed and dated, written informed consent form (ICF) prior to any
mandatory study specific procedures, sampling, and analyses and according to
international guidelines and/or applicable European Union (EU) guidelines.

3. Provision of signed and dated written genetic informed consent in patients that agree
to participate in the genetic sampling, prior to collection of sample for genetic
analysis.

4. Female or male patients aged 18 to 75 years inclusive, at the time of signing the ICF.

5. Patients with bilateral sinonasal polyposis that, despite treatment with a stable dose
of intranasal corticosteroids (INCS) for at least 4 weeks prior to V1, in addition to
history of treatment with systemic (SCS -oral, parenteral) or prior surgery for nasal
polyposis (NP), have severity consistent with a need for surgery as described by:

- A minimum total Nasal Polyp Score (NPS) of 5 out of a maximum score of 8 (with a
unilateral score of at least 2 for each nostril) at V1, and continuously
maintained at V2 to meet the randomization criterion, as determined by the study
Imaging Core Lab;

- Ongoing symptoms for at least 12 weeks prior to V1;

- Patient-reported moderate to severe nasal blockage score (NBS) 2 or 3 over the
2-weeks prior to V1 (2-week recall assessment of symptoms, scores 0-none to
3-severe).

6. SNOT-22 total score ≥ 30 at enrolment.

Patient must meet the following criteria (points 7-10) at the randomization visit:

7. At least 8 days of evaluable daily diary data in the 14-day period prior to
randomization (baseline bi-weekly mean score collected from study Day -13 to study Day
0).

8. At randomization, a bi-weekly mean NBS ≥ 1.5.

9. SNOT-22 total score ≥ 30 at randomization.

10. At least 70% compliance with INCS during the run-in period based on daily diary.

11. Patients with a minimum weight of 40kg.

12. Negative serum pregnancy test result and a negative urine pregnancy test at
randomization for female patients of childbearing potential.

13. Women of childbearing potential (WOCBP) must use an effective form of birth control as
defined in the Clinical Study Protocol (CSP).

15. Male subjects who are sexually active must be surgically sterile at least one year
prior to Visit 1 or must use an adequate method of contraception (condom or condom with
spermicide depending on local regulations) from the first dose of IP until 16 weeks after
their last dose. Men with a partner or partners who is (are) not of childbearing potential
are exempt of these requirements

Exclusion Criteria:

1. Patients who have undergone any nasal and/or sinus surgery within 3 months prior to
V1.

2. Patients with conditions or concomitant disease that makes them non evaluable for the
co-primary efficacy endpoint such as:

- Unilateral antrochoanal polyps;

- Nasal septal deviation that occludes at least one nostril;

- Acute sinusitis, nasal infection, or upper respiratory infection at screening or
in the 2 weeks before screening;

- Current rhinitis medicamentosa;

- Allergic fungal rhinosinusitis (AFRS) or Allergic fungal sinusitis (AFS);

- Nasal cavity tumors.

3. Clinically important comorbidities that could confound interpretation of clinical
efficacy results including, but not limited to: active upper or lower respiratory
tract infection, cystic fibrosis, primary ciliary dyskinesia, eosinophilic diseases
other than asthma (e.g. allergic bronchopulmonary aspergillosis/mycosis, eosinophilic
granulomatosis with polyangitis [Churg-Strauss syndrome], hypereosinophilic
syndromes), granulomatosis with polyangitis (Wegener's granulomatosis), Young's
syndrome, etc.

4. Any disorder, including but not limited to: cardiovascular, gastrointestinal, hepatic,
renal, neurological, musculoskeletal, infectious, endocrine, metabolic,
haematological, psychiatric, or major physical impairment that is not stable in the
opinion of the Investigator or AstraZeneca and could:

- Affect the safety of the patient throughout the study;

- Influence the findings of the studies or their interpretations;

- Impede the patient's ability to complete the entire duration of study.

5. Patients experiencing an asthma exacerbation requiring systemic (oral and/or
parenteral) corticosteroids treatment or hospitalization (>24hrs) for treatment of
asthma within 4 weeks prior to V1.

6. History of anaphylaxis to any biologic therapy or vaccine.

7. Known history of allergy or reaction to any component of the Investigational Product
(IP) formulation.

8. History of Guillain-Barré syndrome.

9. A helminth parasitic infection diagnosed within 24 weeks prior to V1 and has not been
treated with, or has failed to respond to standard of care therapy.

10. Current malignancy, or history of malignancy, except for: - Patients who have had
basal cell carcinoma, localized squamous cell carcinoma of the skin, or in situ
carcinoma of the cervix are eligible provided that patient is in remission and
curative therapy was completed at least 12 months prior to V1; - Patients who have had
other malignancies are eligible provided that the patient is in remission and curative
therapy was completed at least 5 years prior to V1.

NOTE: Hormonal therapy is allowed. As long as the cancer is in remission for 5 years,
the patient is eligible.

11. Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality
obtained during the screening/run-in period, which may put the patient at risk or
interfere with study assessments.

12. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology
(confirmed by additional testing, e.g. hepatitis C RNA test, if indicated), or a
positive medical history for hepatitis B or C (Note: Patients with history of
hepatitis B vaccination without history of hepatitis B are allowed to enroll).

13. History of known immunodeficiency disorder, including a positive human
immunodeficiency virus (HIV) test.

14. Infection requiring systemic antibiotics (Ab) within 14 days prior to V1

15. Use of immunosuppressive medication (including but not limited to: methotrexate,
troleandomycin, cyclosporine, azathioprine, or any experimental anti-inflammatory
therapy) within 3 months prior to V1.

16. Receipt of any marketed or investigational biologic products (monoclonal or polyclonal
antibody) within 6 months or 5 half-lives prior to the date informed consent, is
obtained, whichever is longer, prior to V1 and during the study period. This also
applies to patients who previously participated in clinical studies and were treated
with monoclonal antibodies (e.g. mepolizumab, reslizumab, dupilumab, omalizumab). Note
that this restriction do not apply to patients, who are confirmed to have only
received treatment with placebo.

17. Previous receipt of benralizumab.

18. Receipt of immunoglobulin or blood products within 30 days prior to V1.

19. Receipt of live attenuated vaccines 30 days prior to the date of randomization.

20. Receipt of any investigational drug within 30 days or 5 half-lives whichever is longer
prior to randomization.

21. Receipt of systemic corticosteroid 4 weeks prior to V1, or a scheduled systemic
corticosteroid treatment during the study period.

NOTE: Sustained release steroids (e.g. Kenalog [Triamcinolone acetonide]) or depot
injections require minimum 6 weeks washout prior to V1.

22. Receipt of leukotriene antagonist/modifiers for patients who were not on a continuous
stable dose for ≥30 days prior to V1.

23. Concurrent enrolment in another clinical drug interventional trial.

24. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 3 times the
upper limit of normal (ULN) confirmed during screening period.

25. Previous randomization in the present study.

26. Planned major surgical procedures or scheduled NP surgery at the time of the study
enrolment and randomization.

27. Initiated or is being maintained on an aspirin desensitization regimen for the
management of aspirin exacerbated respiratory disease (AERD) at the time of study
enrolment or during the run-in period.

28. For women only - currently pregnant (or intend to become pregnant), breastfeeding or
lactating.